Oxo-tetrahydrofuran-carboxylic acids



Patented Mar. 7, 1950 UNITED STATES. PATENT OFFICEOX-TETRAHYDROFURAN-CARBOXYLIC ACIDS Chester J. Cavallito, Ravena, N. Y.,assignor to Sterling Drug Inc., Wil

ration of Delaware mington,-' DeL, a corpov. 2

No Drawing. Application June 1, 1948,

Serial No. 30,520

eral formula R: 0 0 V H L B2 OOOH where R1 is a higher alkyl radicalcontaining 10-18 carbon atoms and R2 is a member of the group consistingof hydrogen and lower alkyl radicals containing 1-4 carbon atoms. Thesecompounds are prepared conveniently by heating an ester of a3-sodio-5-R2-2-oxo-tetrahydrofuran-3-carboxylic acid with a higher alkylhalide, hydrolyzing the B-higheralkyl-5-Rz-2-oxo-tetrahydrofuran-3-carboxylic acid ester thus obtainedwith caustic alkali, preferably alcoholic sodium or potassium hydroxidesolution, acidifying the resulting reaction mixture, and separatingtherefrom the 3-higher alkyl-5-Rz-Z-oxo-tetrahydrofuran-3- carboxylicacid thus produced. Alternatively, the intermediate 3-higheralkyl-5-Rz-2- oxo-tetrahydrofuran-B-carboxylic acid ester isobtained bytreating the appropriate ethylene oxide with a (higher alkyl) malonicester, but in general this method is less satisfactory than thepreviously-described method due to isolation diffi culties.

The 3 sodio 5 R2 2 0x0 tetrahydrofuran-3-carboxylic acid esters used asthe starting materials in preparing the compounds of my vention arereadily obtained by treating ethyl sodio-malonate with an Rz-substitutedethylene oxide according to the method of Traube and Lehmann, Ber., 34,1977 (1901). The higher alkyl halides employed in alkylating thesestarting materials can be either the straight or branched chain alkylcompounds, but, for reasons of economy, usually it will be foundpreferable to use the n-alkyl halides.

The new carboxylic acids of my invention have both a bactericidal and abacteriostatic action. They are active against gram-positive bacteria,

9 Claims. (Cl. 260344) stituted ammonium ions.

anaerobic bacteria, and acid-fast bacteria, being especially activeagainst the latter two groups of organisms which inc1ude,'for example,CZ. welchi and M. tuberculosis hominis. In contrast with other types oforganic acids which, in the form of salts or esters, are effectiveagainst acid-fast bacteria, such as chaulmoogric acid and derivativesthereof, my new compounds are sufiiciently soluble in water and aqueousmedia at pH ca. '7

*to obtain inhibitory concentration levels, for example concentrationsof 0.2% to 1%. These tetrahydrofuranones produce a marked surfacetension-lowering effect" and there is a close parallel between'theanti-bacterial activity and the ability to lower surface tension. Thesize of the 3-higher-alky1 substituent has an important im fiuence onthe anti-bacterialactivity of the com;,-,-. pounds, the C14 alkyl"groups representing'the optimum'size in contributing to theantibacterial activity. l

- My compounds areefiective in the .form of the free acids orwateresoluble salts thereof with relatively non-toxic cations, such asalkali metal, alkaline earth metal, and ammonium or sub-.

Thus, in some instances,-it may be convenient to employ the sodium,potassium, lithium, calcium, magnesium, ammonium, or diethylammoniumsalts instead of the free acids. These salts are'easily prepared, forexample,- by dissolvingthe acidin hot water and adding the calculatedquantity of the appropriate alkali metal or alkaline earth base, or

other base. v

M invention is illustrated by the following examples without, however,being limited thereto. The surface tension values-noted for thecompounds in these examples are those values obtained with a Du Nouyinterfacial tensiometer using as a solvent a 0.1 molar potassiumphosphate buffer of pH '7, the solvent surface tension being 71.9 dynesper cm.

EXAMPLE 1 3-n -he:radecyl5-mcthyl-z-omo-tetrahydro jumn-3-carbowylicacid 19.0 g: of ethyl 3-sodio-5-methyl-2-oxo-tetrahydrofuran-3-carboxylate, prepared by interacting 1,2-propylene oxidewith ethyl sodio-malonate using the procedure of Traube and Lehmann(10c.

cit.) is dissolved in 350 ml. 'of anhydrous ethanol and 30 g. ofn-hexadecyl bromide is added to the solution. The reaction mixture isrefluxed for about three hours. The resulting alkylation product issaponified with 150 ml. of hot 5% alcoholic potassium hydroxidesolution. The hydrolysis mixture is'acidified with 10% sulfuric acidsolution andthe acidified mixture is diluted with water. The precipitatewhich forms is 3-nhexadecyl 5 methyl 2 oxo tetrahydrofuran-3-carboxylicacid, which when recrystallized from ethanol melts at 60-63 C. The yieldis 8.0 g. The surface tension of a phosphate buffer solution of thecompound atla concentrationv of 3 10 millimoles per cc. is 37.6dynes'per cm.

In the above example, when an equivalent amount of ethyl3-sodio-5-ethyle2-oxo tetrahy drofuran-3-carboxylate (prepared byinteract ing 1,2-butylene oxide with ethyl sodio-malonate') issubstituted for the ethyl 3-sodio-5-methyl-2-oxo-tetrahydrofuran-3-carboxylate, there is obtained as the finalproduct B-n-hexadecyl-S- ethyl-2-oxo-tetrahydrofuran-3-carboxylicacid.

EXAMPLE 2 B-tetradecyl-S-methyl-Z-o:z:o-ietrahydrojurun- 3-carboxylic,acid.

CH2 0 O V 1 H. C O OH 2)1s Ha Employing a procedure similar to:- thatdescribed' in'lilxample 1, 1517' g; offethyl' 3 -,-sodio'-5+methyl-2-0x0-tetrahydrofuran 3 -carboxylate= is alk-ylated by treatmentwith" 14:0vg. of: n-tetra decyl bromide and the resulting ethyl3'-tetradecyl 5 methyl 2 oxo tetrahyd'rofuran- 3-carboxylate issaponified and acidified. There-is EXAMPLEv 33-n'-tetradecyl-2-orco-teti'ahydrofumm 3-carboxylic acid" H C 0 OH'Employing a. procedure similar to that described in Example 1, 18.0 g.of ethyl 3'-sodio- 2-oxo-tetrahydrofuran-3-carboxylate is. alkylated bytreatment with 27.7 g. of n-tetradecyl" bromide and the resulting ethyl3-n-tetradecyl- 2-oxo-tetrahydrofuran3-carboxylate is saponified andacidified. There is thus obtained, after crystallization of the productfrom petroleum ether, 12.7 g. of 3-n-tetradecyl-2 oxo-tetrahydro'-furan-B-carboxylic acid, M. P;. 82-83 C. The surface tension of aphosphate buffer solution of the compound at a concentration of 3 X 10'millimoles per cc. is 35.0 dynes per cm.

The same final product is obtained when an equivalent amount ofn-tetradecyl iodide is subexample.

4 EXAMPLE;

3-n-dodecyZ-2-o:co-tetrahydrojuran- 3-carbomylic acid To a solution of18 g. of ethyl 3-sodio-2-oxotetrahydrofuran-3carboxylate in 250 ml. ofan hydrous ethanol is added 20 g. of n-dodecyl chloride and the mixtureis refluxed for about eight hours; This alkylation product thus formed,which is ethylv 3en-dodecyl-2-oxo-tetrahydrofuran-B-carboxylate, isisolated, and then saponified', and thesaponification mixture acidifiedby a-procedure similar to that described in Example 1. There is thusobtained, as a precipitate, 2.1 g. of3-n-dodecyl-2-oxo-tetrahydrofuran-3-carboxylic,acid, which whencrystallized from petroleum ether melts at78-7 9 C. The surface tensionof aphosphate bufier solution of the compound at a concentration of 3X10millimoles per cc. is 68.1 dynesper. cm.

EXAMPLE 5 3 -ndecyl-Z-ozco-tetrahydrofuran- 3-carbomylic acid Using aprocedure similar to that described in Example 1, 15.0 g. of3-ndecyl-2-oxo-tetrahydrofurani-3rcarboxylic acid, M. P. '7577 0., isobtained, starting with 27 g. of ethyl 3-sodio-2-oxof-tetrahydrofuran-3-carboxylate and 22 g. of

' nadecylbromide. The-surface tension of a phosphatebufier solution ofthe compound at a concentration of 3X10 millimoles per cc. is 70.3dynes: per cm.

EXAMPLE 6 3-n-tridecyl-Z-oxo-tertrahydrofumn- 3-carboxylic acid is 43.3dynes per cm.

EXANIPLE 7 3-n-tridecyl-2-oa:o-tetrahydrofuran- 3-carbozrylic acid 0 0 UH V-coon (CH2)|5-CH3 14.7" g. of; 3.-n-hexadecyl2-oxortetrahydrowhere R1is a higher alkyl radical containing 10-18 carbon atoms and R2 is amember of the group consisting of hydrogen and lower alkyl radicalscontaining 1-4 carbon atoms; and watersoluble salts thereof.

2. A 3 tetradecyl 2 oxo-tetrahydrofuran- S-carboxylic acid having theformula R: O O

H C OH where R1 is a tetradecyl radical and R2 is a member of the groupconsisting of hydrogen and lower alkyl radicals containing 1-4 carbonatoms; and water-soluble salts thereof.

3. A 3 higher alkyl-z-oxo-tetrahydrofuran- 3-carboxylic acid having theformula 0 U 11 -OOOH where R1 is a higher alkyl radical containing 10-18carbon atoms; and water-soluble salts thereof.

4. A 3-n-tetradecy1-2-oxo-tetrahydrofuran-3- carboxylic acid having theformula 0 0 i V H -43 OOH (CHz)n-CH| and melting at 82-83 0.; andwater-soluble salts thereof.

5. A 3-n-hexadecy1-2-oxo-tetrahydrofuran-3- carboxylic acid having theformula 0 o HLV H 1:000

ibs-CH: and melting at 80-82 0.; and water-soluble salts thereof.

6. The process for preparing a 3-higher alkyl-5-Rz-2-oxo-tetrahydrofuran 3 carboxylic acid, where R2 is a member ofthe group consisting of hydrogen and lower alkyl radicals containing 14carbon atoms, which comprises heating an ester of a3-sodio-5-Rz-2-oxo-tetrahydrofuran-3-carboxylic acid with a higher alkylhalide containing 10-18 carbon atoms; hydrolyzing the 3-higheralkyl-5-Rz-2-oxo-tetrahydrofuran 3 carboxylic acid ester thus obtainedwith caustic alkali; acidifying the resulting reaction mixture; andseparating therefrom the 3-higher a1kyl-5-R2-2-oxo-tetrahydrofuran-3-carboxylic acid thus produced.

7. A 3 n-tetradecyl 5 methy1-2-oxo-tetrahydrofuran-3-carboxylic acidhaving the formula CH: O O

H -COOH and melting at 64-67 0.; and water-soluble salts thereof.

8. A 3 n hexadecyl-5-methyl-2-oxo-tetrahydrofuran-3-carboxylic acidhaving the formula CH: O O

H -C O OH and melting at -63 0.; and water-soluble salts thereof.

9. A 3 n dodecyl-2-oxo-tetrahydrofuran-3- carboxylic acid having theformula 0 0 U H -o 0 on No references cited.

Certificate of Correction Patent N 0. 2,499,986 v March 7, 1959 CHESTERJ. OAVALLITO It is hereby certified that error appears in the printedspecification of the above numbered patent requiring correction asfollows: v

Column 4, line 67, for that portion of the title of Example 7, reading3'n tridecy read 3nhexadecyl;

and that the said Letters Patent should be read with this correctiontherein that the same may conform to the record of the case in thePatent Qffice. V m

Signed and sealed this 20th day of June, A. D. 1950. 1

[SEAL] THOMAS F. MURPHY,

Assistant flommz'ssz'oner of Patents.

1. A 3-HIGHER ALKYL-2-OXO-TETRAHYDROFURAN3-CARBOXYLIC ACID HAVING THE FORMULA. 